Alkyl-and piperidine-substituted benzimidazole derivatives

ABSTRACT

A compound of general formula 1a 
                         
wherein R 1 , R 5 , R 6 , A, B, Y, i, j and m are defined as in the description and claims.
 
     It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates generally to novel benzimidazole-derivatives andtheir use as modulators of chemokine receptor activity, pharmaceuticalcompositions containing the same, and methods of using the same asagents for treatment and prevention of inflammatory diseases such asasthma and allergic diseases, as well as autoimmune pathologies such asrheumatoid arthritis and atherosclerosis.

2. Background Information

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338,436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)).

There are two major classes of chemokines, CXC and CC, depending onwhether the first two cysteines in the amino acid sequence are separatedby a single amino acid (CXC) or are adjacent (CC). The CXC chemokines,such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1a, MIP-1 (3, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and-3) are chemotactic for, among other cell types, macrophages, Tlymphocytes, eosinophils, dendritic cells, and basophils. There alsoexist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines),and fractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seventransmembrane-domain proteins (reviewedin Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed“chemokine receptors.” On binding their cognate ligands, chemokinereceptors transduce an intracellular signal through the associatedtrimeric G proteins, resulting in, among other responses, a rapidincrease in intracellular calcium concentration, changes in cell shape,increased expression of cellular adhesion molecules, degranulation, andpromotion of cell migration. There are at least ten human chemokinereceptors that bind or respond to CC chemokines with the followingcharacteristic patterns: CCR1 (or “CKR-1” or “CC-CKR-1”) [MIP-1a, MCP-3,MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or“CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP2, MCP-3,MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756(1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or“CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1a, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CCCKR-5”) [MIP-1a, RANTES, MIP-1p] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[1-309, TARC, MIP-1p] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpes viruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR-4, CCR-2, CCR-3, CCR-5 and CCR-8, can act as coreceptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, the chemokine receptor CCR-3 plays a pivotal role in attractingeosinophils to sites of allergic inflammation and in subsequentlyactivating these cells. The chemokine ligands for CCR-3 induce a rapidincrease in intracellular calcium concentration, increased expression ofcellular adhesion molecules, cellular degranulation, and the promotionof eosinophil migration. Accordingly, agents which modulate chemokinereceptors would be useful in such disorders and diseases. In addition,agents which modulate chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR-3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

BACKGROUND ART

WO 01 66525 discloses substituted benzimidazoles or benzotriazoles forthe modulation of the CCR5 receptor for the treatment i.e. HIV 1,inflammatory or immunoregulatory. One can also find in the descriptionthe assumption that the disclosed compounds have potential in thetreatment of asthma or COPD.

BRIEF SUMMARY OF THE INVENTION

A compound of general formula 1a

wherein R¹, R⁵, R⁶, A, B, Y and m are defined as below.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt thereof. Theseand other objects, which will become apparent during the followingdetailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of general formula 1a

wherein

-   -   R¹ is aryl, het or a annelated species thereof, wherein het is a        heterocyclic ring and the annelated species comprises aryl-het-,        het-aryl- or het-het-annelations, each of said aryl or het may        be substituted with one, two or three R²;    -   R² are each independently —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl,        —C₁₋₆-haloalkyl, —C₁₋₆-aralkyl, halogen, —CN, —COOR³, —COR³,        —CONR³R⁴, —NR³R⁴, —NR³COR⁴, —NR³SO₂R⁴, —OR³, —NO₂, —SR³, —SOR³,        —SO₂R³ or —SO₂NR³R⁴;    -   R³ is H, —C₁₋₆-alkyl;    -   R⁴ is H, —C₁₋₆-alkyl;    -   R⁵ is —C₁₋₆-alkyl    -   R⁶ are each independently —C₁₋₆-alkyl, —C₁₋₆-alkoxy,        —C₁₋₆-acyloxy, —C₁₋₆-aralkyl, —C₃₋₆-cycloalkyl, —C₁₋₆-haloalkyl,        —C₁₋₆-thioalkyl, halogen, —OR³, —SR³, —CN, —NO₂, —COOR³, —COR³,        —CONR³R⁴, —NR³R⁴, —NR³COR⁴, —NR³SO₂R⁴, —SOR³, —SO₂R³, —SO₂NR³R⁴,        aryl or het;    -   A is —C₂₋₈-alkylene, optionally substituted with —C₁₋₃-alkyl,        halogen or —OH;    -   B is aryl or het;    -   Y is —CF₂—, —NR⁴—, —O—, —S(O)_(n);    -   n is 0, 1 or 2;    -   m is 0, 1, 2, 3 or 4;        and pharmaceutically acceptable salts thereof.

The compounds herein described may have asymmetric centres. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

Used Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to. In the groups,radicals, or moieties defined below, the number of carbon atoms is oftenspecified preceding the group, for example, —C₁₋₆ alkyl means an alkylgroup or radical having 1 to 6 carbon atoms. In general, for groupscomprising two or more subgroups, the last named group is the radicalattachment point, for example, “thioalkyl” means a monovalent radical ofthe formula HS-Alk-. Unless otherwise specified below, conventionaldefinitions of terms control and conventional stable atom valences arepresumed and achieved in all formulas and groups.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers, of a chemical structure or compound isintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. which release an active parent drug of the presentinvention in vivo when such prodrug is administered to a mammaliansubject. Prodrugs the present invention are prepared by modifyingfunctional groups present in the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound. Prodrugs include compounds of the present inventionwherein a hydroxy, amino, or sulfhydryl group is bonded to any groupthat, when the prodrug of the present invention is administered to amammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

The term “aryl” as used herein, either alone or in combination withanother substituent, means either an aromatic monocyclic system oraromatic multicyclic systems containing carbon atoms. For example, arylincludes a phenyl or a naphthyl ring system, wherein aryl meansgenerally an aromatic system, for example phenyl.

The term “het” as used herein, either alone or in combination withanother substituent, means a monovalent substituent derived by removalof a hydrogen from a five-, six- or seven-membered saturated orunsaturated (including aromatic) heterocycle containing carbon atoms andone, two, three or four ring heteroatoms selected from nitrogen, oxygenand sulfur. Examples of suitable heterocycles include: tetrahydrofuran,thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine,piperazine or

Although generally covered under the term “het”, the term “heteroaryl”as used herein precisely defines an unsaturated heterocycle for whichthe double bonds form an aromatic system. Suitable example ofheteroaromatic system include: pyridine, pyrimidine,

The term “annelated species of aryl or het” as used herein, either aloneor in combination with another substituent wherein the annelated speciespresents as a aryl-het (a), a het-aryl (b) or a het-het (c) annelationmeans a monovalent substituent derived by removal of one hydrogen from

-   -   a) an aromatic monocyclic system or aromatic multicyclic systems        containing carbon atoms, which is annelated to a five-, six- or        seven-membered saturated or unsaturated (including aromatic)        heterocycle containing carbon atoms and one, two, three or four        ring heteroatoms selected from nitrogen, oxygen and sulfur or    -   b) a five-, six-, or seven-membered saturated or unsaturated        (including aromatic) heterocycle containing carbon atoms and        one, two, three or four ring heteroatoms selected from nitrogen,        oxygen and sulfur, which is annelated to an aromatic monocyclic        system or aromatic multicyclic systems containing carbon atoms        or    -   c) a five-, six-, or seven-membered saturated or unsaturated        (including aromatic) heterocycle containing carbon atoms and        one, two, three or four ring heteroatoms selected from nitrogen,        oxygen and sulfur, which is annelated to a five-, six-, or        seven-membered saturated or unsaturated (including aromatic)        heterocycle containing carbon atoms and one, two, three or four        ring heteroatoms selected from nitrogen, oxygen and sulfur.

Suitable examples of an annelated species of aryl or het include:quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl,benzimidazyl or purinyl.

The term “halogen” as used herein means a halogen substituent selectedfrom fluoro, chloro, bromo or iodo.

The term “—C₁₋₆-alkyl” as used herein, either alone or in combinationwith another substituent, means acyclic, straight or branched chainalkyl substituents containing from one to six carbon atoms and includes,for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl,1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

The term “—C₃₋₈-cycloalkyl” as used herein, either alone or incombination with another substituent, means a cycloalkyl substituentcontaining from three to six carbon atoms and includes cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

The term “—C₁₋₆-haloalkyl” as used herein, either alone or incombination with another substituent, means acyclic, straight orbranched chain alkyl substituents containing up to six carbon atomshaving one or more hydrogens substituted for a halogen selected frombromo, chloro, fluoro or iodo. Accordingly “—C₂₋₆-haloalkyl” has thesame meaning with exception that the chain contains two to six carbonatoms. Preferably the term —C₁₋₆-haloalkyl represents —C₁₋₆-fluoroalkylsuch as 2-fluorethyl, 2,2,2-trifluorethyl or perfluorethyl.

The term “—C₁₋₆-alkoxy” as used herein, either alone or in combinationwith another substituent, means the substituent —C₁₋₆-alkyl-O— whereinalkyl is as defined above containing up to six carbon atoms. Alkoxyincludes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy or1,1-dimethylethoxy. The latter substituent is known commonly ast-butoxy.

The term “—C₁₋₆-acyloxy” as used herein, either alone or in combinationwith another substituent, means the substituent —C₁₋₆-alkyl-(CO)O—wherein alkyl is as defined above containing up to six carbon atoms.Acyloxy includes MeCOO—, EtCOO—, ^(n)PrCOO—, ^(i)PrCOO—, ^(n)BuCOO—,^(sec)BuCOO— or ^(tert)BuCOO—.

The term “—C₁₋₆-aralkyl” as used herein, either alone or in combinationwith another substituent, means the substituent -Aryl-C₁₋₆-alkyl-wherein alkyl is as defined above containing up to six carbon atoms.Aralkyl includes benzyl, phenylethyl, phenylpropyl,1-phenyl-1-methylethyl, phenylbutyl or 1-phenyl-1,1-dimethylethoxy.

—C₁₋₆-thioalkyl The term “—C₁₋₆-thioalkyl” as used herein, either aloneor in combination with another substituent, means acyclic, straight orbranched chain alkyl substituents containing up to six carbon atoms anda thiol (HS) group as a substituent. An example of a thioalkyl group isa thiopropyl, e.g., HS—CH₂CH₂CH₂—.

The term “—C₂₋₈-alkylene” as used herein means a divalent alkylsubstituent derived by the removal of one hydrogen atom from each end ofa saturated straight or branched chain aliphatic hydrocarbon containingfrom two to eight carbon atoms and includes, for example,CH₂CH₂C(CH₃)₂CH₂CH₂—. Accordingly “—C₁₋₃-alkylene” has the same meaningwith exception that the chain contains one to three carbon atoms.

PREFERRED EMBODIMENTS

The compounds of the instant application are useful for manufacturing amedicament for the prevention and/or treatment of diseases wherein theactivity of a CCR-3-receptor is involved.

Preferred is the manufacturing of a medicament for treatment of a widevariety of inflammatory, infectious, and immunoregulatory disorders anddiseases, including asthma and allergic diseases, infection bypathogenic microbes (which, by definition, includes viruses), as well asautoimmune pathologies such as the rheumatoid arthritis andatherosclerosis.

Most preferred is the manufacturing of a medicament for the treatment ofe.g. inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graftversus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including Tcell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs.

Preferred are compounds of the general formula 1a wherein:

-   -   R¹ is aryl or het, each optionally substituted with one, two or        three R²;    -   R² are each independently —C₁₋₆-alkyl, —C₁₋₆-haloalkyl, halogen,        —CN, —OR³ or —NO₂;    -   R³ is H or Methyl;    -   R⁵ is —C₁₋₆-alkyl    -   R⁶ are each independently —C₁₋₆-alkyl, —C₁₋₆-alkoxy,        —C₁₋₆-haloalkyl, halogen, —OR³, —CN or —NO₂;    -   A is —C₂₋₈-alkylene;    -   B is aryl;    -   Y is —NH—, —O—, —S(O)_(n)—;    -   n is 0 or 2;    -   m is 0, 1 or 2;        and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of general formula 1b, wherein R¹,R⁵, R⁶, A, B, Y and m are defined as above.

and pharmaceutically acceptable salts thereof. Most preferred arecompounds of general formula 1e,

wherein R⁵ is defined as above and

-   -   R² is —CF₃ or halogen;    -   Hal is halogen        and pharmaceutically acceptable salts thereof.

Most preferred are compounds of the general formula 1a, 1b or 1cwherein:

-   -   R¹ is aryl, both optionally substituted with one, two or three        R²; more preferred R¹ is phenyl, optionally substituted with        one, two or three R², or    -   R² is —CF₃ or halogen, in particular fluoro; or    -   —R⁶ is preferably halogen, in particular fluoro; or    -   A is —C₂₋₈-alkylene or more preferred —CH₂—CH₂—CH₂—; or    -   B is phenyl: or    -   Y is —NH—, —O—, —S—, —SO₂—;    -   m is 1 or 2;        and pharmaceutically acceptable salts thereof.

Particular preferred are compounds of the general formula 1c wherein

-   -   R² is fluoro;    -   R⁵ is —C₁₋₆-alkyl, preferably Methyl, Ethyl, Propyl and Butyl,        more preferably Ethyl and Propyl;    -   Hal is fluoro or chloro;        and pharmaceutically acceptable salts thereof.

Most preferred is a compound of formula 1d

and pharmaceutically acceptable salts thereof.

The compounds of formula 1a, 1b, 1c or 1d can be prepared using thereactions and techniques described below. The reactions are performed ina solvent appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention. It willalso be recognized that another major consideration in the planning ofany synthetic route in this field is the judicious choice of theprotecting group used for protection of the reactive functional groupspresent in the compounds described in this invention. An authoritativeaccount describing the many alternatives to the trained practitioner isGreene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons,1991).

Preparation

Compounds of the general formula 1a are prepared by adding a ring B,substituted at least by one nitro-function and a suitable leaving group(LG=i.e. F, Cl) in ortho-position.

After coupling reaction, the nitro function is reduced by e.g. Hydrogenin presence of a Platinum/Charcoal catalyst, Fe/HCl, SnCl₂ orSodiumdithionite (Na₂S₂O₄) to a free amine group.

In the next step of the reaction, the resulting amine function isconverted into an amide group and thereafter in the same or a separatestep transformed in a ring-closing reaction to an imidazole derivative.

wherein the whole process R⁵, R⁶, B, W, i, j, k, l and m are defined asabove.

After this, the protecting benzyl group of the piperidine is removed andpreferably, the compounds of general formula la are prepared by reactionof a compound of general formula 2

with a compound of the general formula 3.

wherein R¹, R⁵, R⁶, A, B, X, W, i, j, k, l and m are defined as forgeneral formula la above and LG is a suitable leaving group e.g. ahalogen, triflate, tosylate or brosylate.

As will be appreciated by one of skill in the art, numerousmodifications and variations of the present invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described herein.

Example 1 1-Benzyl-4-(4-fluoro-2-nitro-phenylamino)-piperidine

2,5-Difluoro-nitrobenzene (21.5 g), 1-benzyl-4-amino-piperidine (52.3 g)and N-methyl-piperidone (100 ml) were stirred at 100° C. for 3 h. Aftercooling the mixture was partitioned between water and ethyl acetate andthe aqueous layer was extracted twice with ethyl acetate. The combinedorganic layers were extracted 5 times with water, and the solvent wasevaporated in vacuo. The target compound was crystallized from methanolto yield 38.7 g of the title compound as orange crystals (mp. 86-87°C.).

Example 2 1-Benzyl-4-(2-amino-4-fluorophenylamino)-piperidine

1-Benzyl-4-(4-fluoro-2-nitrophenylamino)-piperidine (10.1 g) weredissolved in 1:1 THF-methanol (150 ml) and hydrogenated with Pt/C (1.5g, 10%) at room temperature for 1.5 h. The catalyst was then removed byfiltration, and the filtrate evaporated to yield 9.1 g of the titlecompound as an oil. The compound was used without further purification.

Example 3N-[2-(1-Benzyl-piperidin-4-ylamino)-5-fluorophenyl]-propionamide

To a stirred solution of1-Benzyl-4-(2-amino-4-fluoro-phenylamino)-piperidine (6 g) in ethylacetate (50 ml) at room temperature was added acetic anhydride (3.3 ml).After 2 h, the reaction was concentrated in vacuo, and the crude oilpartitioned between 2:1 DCM and water (150 ml) which was made alkalinewith NaOH(aq). The organic layer was separated, washed with water anddried followed by in vacuo concentration to yield 7 g of the titlecompound as a yellow oil. The compound was used without furtherpurification.

Example 4 1-(1-Benzyl-piperidin-4-yl)-2-ethyl-5-fluoro-1H-benzimidazole

N-[2-(1-Benzyl-piperidin-4-ylamino)-5-fluorophenyl]-propionamide (7 g)in glacial acetic acid (70 ml) was heated at reflux for 1 h. Aftercooling the residue was dissolved in ethyl acetate (100 ml) and water(50 ml) was then added. The mixture was made alkaline with K2CO3, andthe organic layer separated, washed with water, then dried andconcentrated in vacuo. The resulting oil was purified by flashchromatography (9:1 DCM:MeOH) to yield 6.4 g of the title compound.

Example 5 2-Ethyl-5-fluoro-1-piperidin-4-yl-1H-benzimidazole

1-(1-Benzyl-piperidin-4-yl)-2-ethyl-5-fluoro-1H-benzimidazole (6.4 g) inmethanol (100 ml) was hydrogenated with Pd/C (10%, 1.5 g) at roomtemperature for 8 h. The catalyst was removed and the filtrate wasevaporated and dissolved in ethanol. The solution was acidified withconc. HCl(aq) and recrystallised by the addition of acetone. Thisyielded 5.3 g of the title compound as colourless crystals.

¹H-NMR (DMSO-d₆) δ [ppm]=1.40 (3H), 2.09-2.15 (2H), 2.81-2.94 (2H),3.10-3.22 (2H), 3.22-3.29 (2H), 3.41-3.51 (2H), 4.99-5.11 (1H), 7.40(1H), 7.69 (1H), 8.56 (1H), 9.30 (1H), 10.03 (1H).

Example 6 1-(3-Bromo-propylsulfanyl)-4-fluoro-benzene

4-Fluorothiophenol (5.3 ml), 1,3-dibromo-propane (15.3 ml), K₂CO₃ (14 g)were dissolved in CH₃CN (100 ml) and refluxed for 3 h. The insolublesalts were removed, the solvent was evaporated and the residue dissolvedin ethyl acetate (70 ml). The solution was extracted with diluted NaOHand water, dried and the solvent evaporated in vacuo. The residue waspurified by distillation to yield 8 g of the title compound as acolourless oil. Bp. 150-155° C. @ 20 mmHg.

Example 72-Ethyl-5-fluoro-1-{1-[3-(4-fluorophenylsulfanyl)-propyl]-piperidin-4-yl}-1H-benzimidazole

To a solution of 2-Ethyl-5-fluoro-1-piperidin-4-yl-1H-benzimidazole (5.4g) in DMF (30 ml) was added 1-(3-bromo-propylsulfanyl)-4-fluoro-benzene(5.7 g), K₂CO₃ (3.2 g) and KI (150 mg). The reaction was stirred at 90°C. for 1 h. After cooling the mixture was poured into water (50 ml) andwas extracted with ethyl acetate (2×50 ml). The organic layer was washedwith water (2×40 ml), dried and concentrated in vacuo. The resulting oilwas purified by flash chromatography (97:3 DCM:MeOH), and the HCl salt(7.5 g) of the title compound obtained by treatment of the purified oilwith conc. HCl(aq) in an isopropanol-acetone solvent mixture, followedby recrystallisation from acetone-MeOH. Mp. 252-255° C.

According to the synthetic route above the following examples wereprepared:

Example 82-Ethyl-1-{1-[3-(4-fluorophenylsulfanyl)-propyl]-piperidin-4-yl}-1H-benzimidazole

To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.5g) and 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.5 g) in DMF (5 ml)was added K₂CO₃ (1.0 g) and KI (0.05 g). The mixture was heated at 100°C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added andthe mixture extracted with ethyl acetate (80 ml), and the organic layerseparated and washed with water. This was further dried and concentratedin vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) toyield 0.6 g of the title compound as colourless crystals. Mp. 182-184°C.

Example 92-Butyl-1-{1-[3-(4-fluorophenylsulfanyl)-propyl]-piperidin-4-yl}-1H-benzimidazole

To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.2g) and 2-butyl-1-piperidin-4-yl-1H-benzimidazole (0.3 g) in DMF (5 ml)was added K₂CO₃ (0.6 g) and KI (0.05 g). The mixture was heated at 100°C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added andthe mixture extracted with ethyl acetate (80 ml), and the organic layerseparated and washed with water. This was further dried and concentratedin vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) toyield 0.3 g of the title compound as colourless crystals. Mp. 159-161°C.

Example 10{3-[4-(2-Ethylbenzimidazol-1-yl)-piperidin-1-yl]-propyl}-(4-fluorophenyl)-amine

To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.6g) and (3-chloropropyl)-(4-fluorophenyl)amine (0.4 g) in DMF (7 ml) wasadded K₂CO₃ (1.1 g) and KI (0.1 g). The mixture was heated at 100° C.for 2 h, and then allowed to cool to rt. Water (50 ml) was added and themixture extracted with ethyl acetate (80 ml), and the organic layerseparated and washed with water. This was further dried and concentratedin vacuo. The oil was purified by flash chromatography (95:5 DCM:MeOH),and the solid recrystallised from ether to yield 0.3 g of the titlecompound as colourless crystals. Mp. 121-124° C.

Example 112-Ethyl-1-{1-[3-(4-fluorobenzenesulfonyl-)propyl]-piperidin-4-yl}-1H-benzimidazole

To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazoledihydrochloride (3.02 g) and1-(3-chloropropane-1-sulfonyl)4-fluorobenzene (2.6 g) in 3:1 THF-DMF (25ml) was added NaHCO₃ (2.9 g), KI (0.3 g) and HMPT (5 ml). The mixturewas heated at reflux for 2 h, and then allowed to cool to rt. Water (100ml) was added and the mixture extracted with ethyl acetate (2×80 ml),and the organic layer separated and washed with water. This was furtherdried and concentrated in vacuo. The oil was purified by flashchromatography and the free base converted to the hydrochloride salt byaction of HCl in ethanol. The solid was recrystallised fromethanol-petroleum ether to yield 2.0 g of the title compound ascolourless crystals. Mp. 212-216° C.

Example 121-{1-[3-(4-Fluorophenoxy)-propyl]-piperidin-4-yl}-1H-benzimidazole

To a stirred solution of 1-piperidin-4-yl-1H-benzimidazole (4.02 g) and1-(3-chloropropoxy)-4-fluorobenzene (4.16 g) in DMF (50 ml) was addedK₂CO₃ (4.1 g) and KI (0.2 g). The mixture was heated at 90° C. for 2 h,and then allowed to cool to rt. Water (100 ml) was added and the mixtureextracted with ethyl acetate (2×80 ml), and the organic layer separatedand washed with water. This was further dried and concentrated in vacuo.The free base converted to the hydrochloride salt by action of HCl inethanol. The solid was recrystallised from ethanol-diethylether to yield4.7 g of the title compound as colourless crystals. MP. 233-235° C.

Method of Treatment

Accordingly, the present invention is directed towards compounds whichare useful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited. Forexample, eosinophilic infiltration to inflammatory sites (e.g., inasthma or allergic rhinitis) can be inhibited according to the presentmethod. In particular, the compound of the following examples hasactivity in blocking the migration of cells expressing the CCR-3receptor using the appropriate chemokines in the aforementioned assays.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graftversus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including Tcell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.

Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The CCR-3 receptor binding test is based on a K562 cell line (leukemiamyelogenic blast cells) transfected with the human chemokine receptorCCR-3 (hCCR-3-C1). The cell membranes were prepared by disrupting thehCCR-3 transfected K562 cells by nitrogen decomposition andcentrifugation at 40000 g, 4° C. for 1 h. The membranes werere-suspended in the SPA incubation buffer without bovine serum albuminfor storage in aliquots at −80° C.

The CCR-3 receptor binding assay with the radioligand¹²⁵Jodine-eotaxin-1 was performed in a Scintillation Proximity Assay(SPA) design. Cell membranes of hCCR-3 C1 cells were diluted in suitableconcentrations (0.5-5 ug protein/well) in 96 well microtiter plates(1450-401, Wallac).

The test incubation mixture comprising 60 μl of the membrane suspension,80 μl of the Wheat Germ Agglutinin coated PVT beads (organicscintillator, Amersham Pharmacia biotech) in a concentration of 0.4 mgand 40 μl of radiolabelled ¹²⁵J rhEotaxin (Amersham, IM290) wereincubated with 20 μl of the test compound (dissolved in DMSO dilutions)for 2 hours. The SPA incubation buffer contained 25 mM HEPES, 25 mMMgCl₂ 6×H₂O, 1 mM CaCl₂ 2×H₂O and 0.1% bovine serum albumin. Includedwere controls for specific binding (no displacer added) and non-specificbinding by adding unlabelled rhEotaxin (R&D Systems) or a test compound.Bound radioactivity was determined by scintillation counter (Micro Beta“Trilux”, Wallac).

Determination of affinity of test compounds (dissociation constantK_(i)) was calculated by iterative fitting of experimental data usingthe law of mass action based program “easy sys” (Schittkowski, Num Math68, 129-142 (1994)).

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR-2 and CCR-3ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 11371143(1997). Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-5 present, or a cellengineered to express a recombinant chemokine receptor, such as CHO orHEK-293. Finally, blood or tissue cells, for example human peripheralblood eosinophils, isolated using methods as described by Hansel et al.,J. Immunol. Methods, 145, 105-110 (1991), can be utilized in suchassays. In particular, the compounds of the present invention haveactivity in binding to the CCR-3 receptor in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 MM or lower in concentration when measured in theaforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.

Pharmaceutical Forms

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of formula 1a that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate diseases, wherein the activity of aCCR-3-receptor is involved, or the progression of this disease.

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermale routes,using transdermale skin patches. When administered in the form of atransdermale delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and colouring agents can also be incorporated into the mixture.Suitable binders include starch, gelatine, natural sugars such asglucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspart-amidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues.

Furthermore, the compounds of the present invention may be coupled to aclass of biodegradable polymers useful in achieving controlled releaseof a drug, for example, polylactic acid, polyglycolic acid, copolymersof polylactic and polyglycolic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and cross linked or amphipathicblock copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit.

In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

Gelatine capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain colouring andflavouring to increase patient acceptance.

In general, water, suitable oil, saline, aqueous dextrose (glucose), andrelated sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of formula 1a, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of formula 1a and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients.

Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

1. A compound of general formula 1a,

wherein R¹ is phenyl, optionally substituted with one, two or three R²;R² are each independently —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl,—C₁₋₆-haloalkyl, —C₁₋₆-aralkyl, halogen, —CN, —COOR³, —COR³, —CONR³R⁴,—NR³R⁴, —NR³COR⁴, —NR³SO₂R⁴, —OR³, —NO₂, —SR³, —SOR³, —SO₂R³ or—SO₂NR³R⁴; R³ is H or —C₁₋₆-alkyl; R⁴ is H or —C₁₋₆-alkyl; R⁵ is—C₁₋₆-alkyl R⁶ are each independently —C₁₋₆-alkyl, —C₁₋₆-alkoxy,—C₁₋₆-acyloxy, —C₁₋₆-aralkyl, —C₃₋₆-cycloalkyl, —C₁₋₆-haloalkyl,—C₁₋₆-thioalkyl, halogen, —OR³, —SR³, —CN, —NO₂, —COOR³, —COR³,—CONR³R⁴, —NR³R⁴, —NR³COR⁴, —NR³SO₂R⁴, —SOR³, —SO₂R³, —SO₂NR³R⁴, aryl orhet; A is —C₂₋₈-alkylene, optionally substituted with —C₁₋₃-alkyl,halogen or —OH; B is aryl or het; Y is —CF₂—, —NR⁴—, —O—, —S(O)—; n is0, 1 or 2; m is 0, 1, 2, 3 or 4; and pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1, wherein R¹ and R⁵ aredefined as in claim 1 and R² are each independently —C₁₋₆-alkyl,—C₁₋₆-haloalkyl, halogen, —CN, —OR³ or —NO₂; R³ is H or —C₁₋₆-alkyl; R⁶are each independently —C₁₋₆-alkyl, —C₁₋₆-alkoxy, —C₁₋₆-haloalkyl,halogen, —OR³, —CN or —NO₂; A is —C₂₋₈-alkylene; B is aryl; Y is —NH—,—O—, —S(O)_(n)—; n is 0 or 2; m is 0, 1 or 2; and pharmaceuticallyacceptable salts thereof.
 3. A compound of general formula 1b,

wherein R¹, R⁵, R⁶, A, Y and m are defined as in claim 1 or 2 andpharmaceutically acceptable salts thereof.
 4. A compound according toany one of the claims 1-3 wherein, Y is —NH—, —O—, —S(O)_(n)—; A is—C₂₋₈-alkylene; and pharmaceutically acceptable salts thereof.
 5. Acompound according to any one of the claims 1-4 wherein, A is—CH₂—CH₂—CH₂—; and pharmaceutically acceptable salts thereof.
 6. Acompound of general formula 1c,

wherein R⁵ is —C₁₋₆-alkyl and R² is —CF₃ or halogen; Hal is halogen; andpharmaceutically acceptable salts thereof.
 7. A compound of generalformula 1d,

and pharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition comprising one or more compounds of formula 1a, 1b, 1c or 1daccording to one of claims 1-7 and a pharmaceutically acceptablecarrier.